Salli Roseffi Nasution

Divisi ginjal-hipertensi
Dept.penyakit dalam FK USU/ RS HAM 19 - 01 - 08
 Hypertension
More Than Just High BP
Hypertension represents a complex syndrome in
which neurohumoral and metabolic abnormalities
influence development and progression of
vascular disease and clinical events
Vascular injury accompanying the hypertension
syndrome is mediated by hemodynamic and non-
hemodynamic factors
Primary hypertension

The pressure required to move blood through the circulatory

bed is provided by the pumping action of the heart ( CO )
and the tone of arteries ( PR )

Blood pressure = Cardiac output X Peripheral resistance

Hypertension = Increased CO And / or Increased PR
Increase in Cardiac output
Increase in fluid volume ( preload )
Increase in contractility from neural stimulation

In established hypertension
Elevated PR and normal CO
 Excess Reduced Endothelium
Genetic
sodium nephron Stress Obesity Derived
alteration
intake number factors

Renal Decreased Sympathetic Renin- Cell

Hyper-
Sodium Filtration Nervous over Angiotensin Membrane
insulinemia
retention surface activity excess alteration

Increased
Venous
fluid
constriction
volume

Increased Increased Functional Structural

preload contractability constriction hypertrophy

Blood Pressure = Cardiac Output X Peripheral Resistance

Hypertension = Increased CO And / or Increased PR
Autoregulation

Some of the factors involved in the control of blood pressure

Excess sodium intake

There is conclusive evidence that dietary salt is positively associated

with BP and that BP can be lowered with reduction in sodium intake
of 40 to 50 mmol (per day ) In both hypertensive and nonhypertensive
persons (Chobanian and Hill, 2000 )

Denton, 1997 : Primitive people from widely different parts of the world
who do not eat sodium have no hypertension, and their
BP does not rise with age, as it does in all industrialized
populations

Dietary chloride
Chloride , may be involved in causing hypertension
Schorr et all, 1996 : The BP rises more with NaCl than with
nonchloride salts of sodium .
 Excess Reduced Endothelium
Genetic
sodium nephron Stress Obesity Derived
alteration
intake number factors

Renal Decreased Sympathetic Renin- Cell

Hyper-
Sodium Filtration Nervous over Angiotensin Membrane
insulinemia
retention surface activity excess alteration

Increased
Venous
fluid
constriction
volume

Increased Increased Functional Structural

preload contractability constriction hypertrophy

Blood Pressure = Cardiac Output X Peripheral Resistance

Hypertension = Increased CO And / or Increased PR
Autoregulation

Some of the factors involved in the control of blood pressure

Reduced nephron number

Brenner et all, 1988

Hypertension may arise from a congenital reduction

in the number of nephrons or in the filtration surface area
per glomerulus, thereby limitating the ability to excrete sodium,
raising the blood pressure.
Definition and Classification of
Hypertension
 Definition and classification of
hypertension: ESH/ESC 2003
Hypertension is defined as blood pressure 140/90
Category mmHgSystolic Diastolic
(mmHg) (mmHg)
Optimal <120 <80

Normal 120-129 80-84

High normal 130-139 85-89

Grade 1 hypertension (mild) 140-159 90-99

Grade 2 hypertension (mod) 160-179 100-109

Grade 3 hypertension (severe) 180 110

Isolated systolic hypertension 140 <90

When a patients systolic and diastolic blood pressures fall into different ESH/ESC Guidelines 2003
categories, the higher category should apply J Hypertens 2003;21:1011-1053
 Definition and classification of
hypertension: JNC VII
Hypertension is defined as blood pressure 140/90 mmHg

Category Systolic Diastolic

(mmHg) (mmHg)
Normal <120 and <80

Prehypertension 120-139 or 80-89

Stage 1 hypertension 140-159 or 90-99

Stage 2 hypertension 160 or 100

JNC VII. JAMA 2003;289:2560-2572

 Definition and classification of
hypertension: WHO/ISH 1999/2003
Hypertension is defined as blood pressure 140/90
Category mmHgSystolic Diastolic
(mmHg) (mmHg)
Optimal <120 <80
Normal <130 <85
High-normal 130-139 85-89
Grade 1 hypertension (mild) 140-159 or 90-99
Subgroup: borderline 140-149 90-94
Grade 2 hypertension 160-179 or 100-109
(moderate)
Grade 3 hypertension (severe) 180 or 110
Isolated systolic hypertension 140 <90
Subgroup: borderline 140-149 <90

When a patients systolic and diastolic blood pressures fall 2003 WHO/ISH Statement on Hypertension.
J Hypertens 2003;21:1983-1992; 1999 WHO/ISH Guidelines for the
into different categories, the higher category should apply Management of Hypertension. J Hypertens 1999;17:151-183
 Prevalence of hypertension*:
North America and Europe
80
Men
70 Women
Prevalence (%)

60 Total
50
40
30
20
10
0

* BP 140/90 mmHg or treatment with antihypertensive medication Wolf-Maier K, et al. JAMA 2003;289:2363-2369
 Prevalence of hypertension: Asia
80
Men
70
Prevalence (%)

Women
60
Total
50
40
30
20
10
0

Gu DF, et al. Hypertension 2002;40:920-927; Singh RB, et al. J Hum Hypertens 2000;14:749-763; Janus ED. Clin Exp Pharmacol Physiol
1997;24:987-988; National Health Survey 1998, Singapore. Epidemiology and Disease Department, Ministry of Health, Singapore.; Lim TO, et al.
Singapore Med J 2004;45:20-27; Tatsanavivat P, et al. Int J Epidemiol 1998;27:405-409; Muhilal H. Asia Pacific J Clin Nutr 1996;5:132-134;
Gupta R. J Hum Hypertens 2004;18:73-78; Asai Y, et al. Nippon Koshu Eisei Zasshi 2001;48:827-836 [in Japanese]
Prevalence of Hypertension* by Age in the General
Population of The United States, 1988-91

Age in years Percentage hypertensive

18 29 4
30 39 11
40 49 21
50 59 44
60 69 54
70 79 64
> 80 65

Average of three blood pressure measurements, at a single visit, 140

mmHG, or 90 mmHg diastolic, or current treatment with an
antihypertensive medication.

Center for Disease Control, National Center for Health Statistics.

 13

Prevalence of hypertension increases with age

Prevalence of HTN (%)

80
70 65.2
60
50
40
29.1
30
20
10 6.7

0
2039 4059 60
SBP/DBP (mmHg)
SBP = systolic BP; DBP = diastolic BP
Estimated non-institutionalised US adults, 19992002
From Centers for Disease Control and Prevention Brown. BMJ 2006;332:8336
 12

Prevalence of hypertension by age and gender

Prevalence of HTN (%)

100
Men Women 80.3
80 71.2
60.3 61.3
60
44.8 42.0
40 32.6
21.2 23.3
20 14.4
9.9
6.2

0
2029 3039 4049 5059 6069 70

Data for established market economies (US, Canada, Spain,

England, Germany, Greece, Italy, Sweden, Australia, Japan) Kearney et al. Lancet 2005;365:21723
 22
Awareness, treatment and control rates for hypertension
are low across all age groups in the US

Estimated size of population

(in millions)
20 18.5 Age 2544 years
16.0 Age 4564 years
15 Age =65

10
7.5 6.9
5.8
4.4 4.2 4.5
5 2.9
3.5
2.8 2.3
1.9 1.7
0.9
0
Total no. No. with HTN, No. with No. with No. with
with HTN but unaware acknowledged treated and treated and
of it untreated uncontrolled controlled
HTN HTN HTN
NHANES III data Hyman and Pavlik. N Engl J Med 2001;345:47986
 23
Approximately 73% of European patients with
hypertension remain untreated

Patients (%) Treated Untreated

100
75 74 74 73 68
80

60

40

20

0
England Sweden Germany Spain Italy

Wolf-Maier et al. Hypertension 2004;43:1017

 24
Approximately 70% of treated patients* in Europe do not
reach blood pressure goal

Patients (%) BP goal achieved BP goal not achieved

100
60 79 71 81 71
80

60

40

20

0
England Sweden Germany Spain Italy

*Treated for hypertension

BP goal is <140/90 mmHg Wolf-Maier et al. Hypertension 2004;43:1017
Hypertension control rates around the
world
<140/90 mmHg (%) <160/95 mmHg (%)
United States 27 Germany 23
France 24 Finland 21
Canada 22 Spain 20
Italy 9 Australia 19
Egypt 8 Scotland 18
England 6 India 9
Korea 5 Zaire 3
China 3
Poland 2

JNC VI. Arch Intern Med 1997;157:2413-2446; Joffres MR, et al. Am J Hypertens 1997;10:1097-1102;
Colhoun HM, et al. J Hypertens 1998;16:747-752; Chamotin B, et al. Am J Hypertens 1998;11:759-762;
Marques-Vidal P, et al. J Hum Hypertens 1997;11:213-220
 Progress in the treatment of
Hypertension

2000s Prevention ?

1990s BP lowering + effect on specific morbidity

1980s Effective of BP lowering in various populations

1970s Does BP lowering improve a patients prognosis ?

1960s Is it possible to effectively decrease the BP?

Stevo Julius, Journal of Hypertension 2000, vol 18 (suppl 3)

 Progress of antihypertensive drugs

Effectiveness and general tolerability

1940s 1950 1957 1960s 1970s 1980s 1990s 2000

Direct Alpha- ARBs

ACE
vasodilators blockers
inhibitors Oral
Peripheral Thiazide Renin
sympatholytics diuretics inhibitor
Central 2
Ganglion agonists
blockers Calcium
Calcium antagonists-
Veratrum antagonists- DHPs
alkaloids non-DHPs
Beta-blockers

DHP, dihydropyridine;
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker
Main classes of antihypertensive drugs

Diuretics
Inhibit the reabsorption of salts and water from kidney tubules
into the bloodstream
Calcium-channel antagonists
Inhibit influx of calcium into cardiac and smooth muscle
Beta-blockers
Inhibit stimulation of beta-adrenergic receptors
Angiotensin-converting enzyme (ACE) inhibitors
Inhibit formation of angiotensin II
Angiotensin II receptor blockers (ARBs)
Inhibit binding of angiotensin II to type 1 angiotensin II
receptors
Renin inhibitor ( Aliskiren )
- Inhitor of human renin
 Renin-angiotensin-aldosterone system
Angiotensinogen
(-)
Renin
Angiotensin I Bradykinin
Angiotensin-
converting
enzyme
Angiotensin II Inactive kinins

BP AT1 AT2
Vasoconstriction Vasodilation
Aldosterone secretion Inhibition of cell growth
Catecholamine release Cell differentiation
Proliferation Injury response
Hypertrophy Apoptosis
Ellis ML, et al. Pharmacotherapy 1996;16:849-860;
BP, blood pressure Carey RM, et al. Hypertension 2000;35:155-163
 Factors influencing BP control

Efficacy

+
Adverse effects

+
Convenience
 Dose-related efficacy and
side-effect profile
Antihypertensive efficacy generally improves with an
increase in dose
Common side effects associated with:
ACE inhibitors cough
CCBs ankle oedema, flushing
Beta-blockers tiredness, impotence
ARBs have demonstrated placebo-like tolerability even at
higher doses

ACE, angiotensin-converting enzyme;

CCB, calcium-channel blocker; ARB, angiotensin II
receptor blocker
 Multiple antihypertensive agents
are needed to achieve target BP
Number of antihypertensive agents
Trial Target BP (mmHg) 1 2 3 4

UKPDS DBP <85

ABCD DBP <75
MDRD MAP <92
HOT DBP <80
AASK MAP <92
IDNT SBP <135/DBP <85
ALLHAT SBP <140/DBP <90

Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;

DBP, diastolic blood pressure; MAP, mean arterial pressure; Lewis EJ, et al. N Engl J Med 2001;345:851-860;
SBP, systolic blood pressure Cushman WC, et al. J Clin Hypertens 2002;4:393-404
 37
Among patients still on therapy after the first year,
50% stop therapy within the next two years

Retrospective, cohort study of the

100 Netherlands community pharmacy records
Continuous antihypertensive

90 (N=2,325)
80
70
users (%)

60
50
Men
40 Women
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Years after first prescription

Van Wijk et al. J Hypertens 2005;23:21017

 Compliance at 1 year with
antihypertensive treatment
70 64 *
* p<0.007 vs ACE inhibitors 58
60
Compliance at 1 year (%)

50
50
43
40 38

30

20

10

0
Diuretics Beta- blockers CCBs ACE inhibitors ARBs

ACE, angiotensin-converting enzyme;

CCB, calcium-channel blocker; ARB, angiotensin II
Bloom BS, et al. Clin Ther 1998;20:671-681
receptor blocker
 Goals of treatment: ESH/ESC 2003

Achieve maximum reduction in total

cardiovascular risk
Treat all reversible risk factors and
associated clinical conditions in addition
to treating raised blood pressure
Target blood pressure <140/90 mmHg
and to lower values, if tolerated
For diabetics, target blood pressure is
<130/80 mmHg
ESH/ESC Guidelines 2003. J Hypertens 2003;21:1011-1053
 Goals of treatment: JNC VII

The SBP and DBP targets are

<140/90 mmHg
The primary focus should be on
achieving the SBP goal
In patients with hypertension and
diabetes or renal disease, the BP goal
is <130/80 mmHg

SBP, systolic blood pressure; DBP, diastolic blood pressure;

BP, blood pressure JNC VII. JAMA 2003;289:2560-2572
TARGET PENURUNAN TEKANAN DARAH:

UMUM, TANPA PENYULIT: <140/80 mmHg

DIABETES : < 130/80 mmHg

GANGGUAN GINJAL : < 130/80 mmHg

PROTEINURIA > 1G/HR : <125/75 mmHg

 Goals of treatment: WHO/ISH 2003
Decisions about the management of
hypertensive patients should be based on
blood pressure levels and the presence of
other cardiovascular risk factors, target organ
damage and associated clinical conditions
In hypertensive patients at low to medium
risk*, the SBP goal is <140 mmHg
In hypertensive patients at high risk*, a target
of <130/80 mmHg is appropriate

* Risk of developing a major cardiovascular event (fatal and nonfatal stroke, and
myocardial infarction)

SBP, systolic blood pressure 2003 WHO/ISH statement on hypertension. J Hypertens 2003;21:1983-1992
 Consequences of Uncontrolled
Blood Pressure

Stroke, hemorrhage
LVH, CHD, CHF
Renal failure
Peripheral vascular disease
Retinopathy

Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment
of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157:2413-2446.
Mancia et al, J Hypertens 2002 vol 20 (suppl 5)
(Modified from Rutan et al)
 Hypertension: A risk factor for
cardiovascular disease
Coronary Stroke Peripheral artery Cardiac
disease disease failure
50
45.5
45
40
Biennial age-adjusted rate

35 Normotensive
per 1,000 subjects

30
Hypertensive

25 22.7
21.3
20
15 13.9
12.4
9.5 9.9
10 7.3
6.2 6.3
5.0
5 3.3 2.4 3.5
2.0 2.1
0
Risk Men Women Men Women Men Women Men Women
ratio: 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0

Kannel WB. JAMA 1996;275:1571-1576

 High Normal BP is Not Benign
Cumulative incidence of CV events* (%)

14 High 14
Men normal Women
12 12
1.6-fold High
Normal 10 2.5-fold normal
10 greater risk
greater risk
8 8

6 Optimal 6
Normal
4 4

2 2
Optimal
0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
Time (yr) Time (yr)

*CV death, MI, stroke, CHF. Age-adjusted risk comparison of High normal versus normal.
Optimal: <120/<80 mm Hg. Normal: 120-129/80-84 mm Hg. High normal: 130-139/85-89 mm Hg.

Vasan RS et al. N Engl J Med 2001;345:1291-1297.

 Millimetres matter

For individuals 40-70 years of age, each

increment of 20 mmHg in systolic BP or
10 mmHg in diastolic BP doubles the risk
of CVD across the entire BP range from
115/75 to 185/115 mmHg

JNC VII. JAMA 2003;289:2560-2572

BP, blood pressure; CVD, cardiovascular disease
 BP Reductions as Small as 2 mmHg Reduce
the Risk of CV Events by up to 10%

Meta-analysis of 61 prospective, observational studies

1 million adults
12.7 million person-years
7% reduction
in risk of IHD
2 mmHg mortality
decrease in
mean SBP 10% reduction
in risk of stroke
mortality

Prospective Studies Collaboration. Lancet 2002;360:1903-1913.

 Millimetres matter

A 2-mmHg reduction in DBP would

result in a 6% reduction in the risk
of
CHD and a 15% reduction in the risk of
stroke and TIAs

DBP, diastolic blood pressure; CHD, coronary heart

disease; Cook NR, et al. Arch Intern Med 1995;155:701-709
TIA, transient ischaemic attack
 Implications of small reductions in DBP
for primary prevention
DBP reduction

7.5 mmHg 5-6 mmHg 2 mmHg

0

-10 -6
Risk reduction (%)

-16 -15
-20
-21
-30

-40 CHD
-38
Stroke

-50 -46

DBP, diastolic blood pressure; CHD, coronary heart disease Cook NR, et al. Arch Intern Med 1995;155:701-709
 12 to 13 mm Hg drop in systolic BP reduces
4-year risk of CAD, stroke, mortality
All-cause
CHD Stroke CVD mortality mortality
0%
Reduction in risk (%)

-10%

-13%
-20% P=0.005
-21%
P<0.0001 -25%
-30%
P<0.001

-40% -37%
P<0.001

Meta-analysis of 10 randomized trials.

He and Whelton, J Hypertens, 1999.
 Hypertension Optimal Treatment (HOT) study

Intensive BP-lowering decreases cardiovascular risk in patients with

hypertension, especially among those with diabetes
Major CV 30
All patients (n=18 790)
events per
Diabetics (n=1501)
1000 patient 25 24.4
years

20 18.6

15
11.9
9.9 10.0 9.3
10

0
90 mmHg 85 mmHg 80 mmHg
Target DBP group

Lancet 1998;351:17551762
 Meta-Analysis: Lower Systolic BP Results
in Slower Rates of Decline in GFR
in Patients With and Without Diabetes
SBP (mm Hg)
130 134 138 142 146 150 154 170 180
0
-2
GFR (mL/min/y)

r = 0.69; P < 0.05

-4
-6
Untreated
-8 hypertension
-10
-12
-14
Parving HH et al. Br Med J. 1989. Moschio G et al. N Engl J Med. 1996.
Viberti GC et al. JAMA. 1993. Bakris GL et al. Kidney Int. 1996.
Klahr S et al. N Eng J Med. 1994. Bakris GL. Hypertension. 1997.
Hebert L et al. Kidney Int. 1994. GISEN Group. Lancet. 1997.
Lebovitz H et al. Kidney Int. 1994.

Bakris et al. Am J Kidney Dis. 2000;36:646

Gagal Ginjal Dalam Hipertensi
 Benefits of Lowering BP in the
Elderly
SHEP STOP-1 (N MRC
(N = 4736) = 1627) (N = 2394)
BP Reduction (mm Hg) 12/4 20/8 12/5
Results (% reduction)
Total mortality 13 43* 3
All stroke 37* 47* 25*
CHD 25* 13 19
All CV events 32* 40* 17*

*P < 0.01.
Myocardial infarction only.

Hansson L. Cardiovasc Drugs Ther. 2001;15:275-279.

 HOT study
Risk of a major cardiovascular event reduced
by 30% in the HOT Study
Achieved DBP
105 100 95 90 85 80 mm Hg
0

5 Optimal DBP
reduction in the
10 HOT Study

15

20

25

30
% risk reduction
 HOT study
Risk of a major cardiovascular event reduced
by 22% in the HOT Study

Achieved SBP
170 160 150 140 130 mm Hg
0

5 Optimal SBP
reduction in the
10 HOT Study

15

20

25

30
% risk reduction
 The lower the target BP

The better preservation of target organ

and the lower mortality
Mudah-mudahan lah
Orangtu mengerti
Yang penting
Tulis . OLMETEC

Terima kasih